Abstract
Much less attention has been paid to Zn2+ in artificial cerebrospinal fluid (ACSF), i.e., extracellular medium, used for in vitro slice experiments than divalent cations such as Ca2+. Approximately 2 mM Ca2+ is added to conventional ACSF from essentiality of Ca2+ signaling in neurons and glial cells. However, no Zn2+ is added to it, even though the importance of Zn2+ signaling in them is recognizing. On the other hand, synaptic Zn2+ homeostasis is changed during brain slice preparation. Therefore, it is possible that not only neuronal excitation but also synaptic plasticity such as long-term potentiation is modified in ACSF without Zn2+, in which original physiology might not appear. The basal (static) levels of intracellular (cytosolic) Zn2+ and Ca2+ are not significantly different between brain slices prepared with conventional ACSF without Zn2+ and pretreated with ACSF containing 20 nM ZnCl2 for 1 h. In the case of mossy fiber excitation, however, presynaptic activity assessed with FM 4–64 is significantly suppressed in the stratum lucidum of brain slices pretreated with ACSF containing Zn2+, indicating that hippocampal excitability is enhanced in brain slices prepared with ACSF without Zn2+. The evidence suggests that low nanomolar concentration of Zn2+ is necessary for ACSF. Furthermore, exogenous Zn2+ has opposite effect on LTP induction between in vitro and in vivo experiments. It is required to pay attention to extracellular Zn2+ concentration to understand synaptic function precisely.
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Teyler TJ (1999) Use of brain slices to study long-term potentiation and depression as examples of synaptic plasticity. Methods 18:109–116
Villers A, Ris L (2013) Improved preparation and preservation of hippocampal mouse slices for a very stable and reproducible recording of long-term potentiation. J Vis Exp 76, e50483
Hille B (1984) Ionic channels of excitable membranes. Sinauer, Sunderland
Stringer JL, Lothman EW (1988) In vitro effects of extracellular calcium concentrations on hippocampal pyramidal cell responses. Exp Neurol 101:132–146
Brown AM, Ransom BR (2002) Neuroprotective effects of increased extracellular Ca(2+) during aglycemia in white matter. J Neurophysiol 88:1302–1307
Wang T, Wang J, Cottrell JE, Kass IS (2004) Small physiologic changes in calcium and magnesium alter excitability and burst firing of CA1 pyramidal cells in rat hippocampal slices. J Neurosurg Anesthesiol 16:201–209
Villers A, Godaux E, Ris L (2012) Long-lasting LTP requires neither repeated trains for its induction nor protein synthesis for its development. PLoS One 7, e40823
Kim NK, Robinson HP (2011) Effects of divalent cations on slow unblock of native NMDA receptors in mouse neocortical pyramidal neurons. Eur J Neurosci 34:199–212
Jones HC, Keep RF (1988) Brain fluid calcium concentration and response to acute hypercalcaemia during development in the rat. J Physiol 402:579–593
Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13:169–182
Alberdi E, Sánchez-Gómez MV, Cavaliere F, Pérez-Samartín A, Zugaza JL, Trullas R, Domercq M, Matute C (2010) Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47:264–272
Bickler PE, Warren DE, Clark JP, Gabatto P, Gregersen M, Brosnan H (2012) Anesthetic protection of neurons injured by hypothermia and rewarming: roles of intracellular Ca2+ and excitotoxicity. Anesthesiology 117:280–292
Abushik PA, Sibarov DA, Eaton MJ, Skatchkov SN, Antonov SM (2013) Kainate-induced calcium overload of cortical neurons in vitro: dependence on expression of AMPAR GluA2-subunit and down-regulation by subnanomolar ouabain. Cell Calcium 54:95–104
Frederickson CJ, Giblin LJ, Krezel A, McAdoo DJ, Muelle RN, Zeng Y, Balaji RV, Masalha R et al (2006) Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion. Exp Neurol 198:285–293
Sensi SL, Paoletti P, Koh JY, Aizenman E, Bush AI, Hershfinkel M (2011) The neurophysiology and pathology of brain zinc. J Neurosci 31:16076–16085
Takeda A, Nakamura M, Fujii H, Tamano H (2013) Synaptic Zn2+ homeostasis and its significance. Metallomics 5:417–423
Takeda A, Fujii H, Minamino T, Tamano H (2014) Intracellular Zn2+ signaling in cognition. J Neurosci Res 92:819–824
Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462
Suh SW, Danscher G, Jensen MS, Thompson R, Motamedi M, Frederickson CJ (2000) Release of synaptic zinc is substantially depressed by conventional brain slice preparations. Brain Res 879:7–12
Fraker PJ, Telford WG (1997) A reappraisal on the role of zinc in life and death decisions of cells. Proc Soc Exp Biol Med 215:229–236
Jankowski-Hennig MA, Clegg MS, Daston GP, Rogers JM, Keen CL (2000) Zinc deficient rat embryos have increased caspase 3-like activity and apoptosis. Biochem Biophys Res Commun 271:250–256
Duffy JY, Miller CM, Rutschilling GL, Ridder GM, Clegg MS, Keen CL, Daston GP (2001) A decrease in intracellular zinc level precedes the detection of early indicators of apoptosis in HL-60 cells. Apoptosis 6:161–172
Seve M, Chimienti F, Favier A (2002) Role of intracellular zinc in programmed cell death. Pathol Biol (Paris) 50:212–221
Verstraeten SV, Zago MP, MacKenzie GG, Keen CL, Oteiza PI (2004) Influence of zinc deficiency on cell-membrane fluidity in Jurkat, 3T3 and IMR-32 cells. Biochem J 378:579–587
Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216
Conforti G, Zanetti A, Pasquali-Ronchetti I, Quaglino DJ, Neyroz P, Dejana E (1990) Modulation of vitronectin receptor binding by membrane lipid composition. J Biol Chem 265:4011–4019
Whiting KP, Restall CJ, Brain PF (2000) Steroid hormone-induced effects on membrane fluidity and their potential roles in non-genomic mechanisms. Life Sci 67:743–757
Pfeiffer CC, Braverman ER (1982) Zinc, the brain and behavior. Biol Psychiatry 17:513–532
Beach RS, Gershwin ME, Hurley LS (1982) Reversibility of development retardation following murine fetal zinc deprivation. J Nutr 112:1169–1181
Sandstead HH (2012) Subclinical zinc deficiency impairs human brain function. J Trace Elem Med Biol 26:70–73
Watanabe M, Tamano H, Kikuchi T, Takeda A (2010) Susceptibility to stress in young rats after 2-week zinc deprivation. Neurochem Int 56:410–416
Takeda A (2011) Zinc signaling in the hippocampus and its relation to pathogenesis of depression. Mol Neurobiol 44:166–174
Takeda A, Iida M, Ando M, Nakamura M, Tamano H, Oku N (2013) Enhanced susceptibility to spontaneous seizures of Noda epileptic rats by loss of synaptic Zn2+. PLoS One 8, e71374
Takeda A, Tamano H (2009) Insight into zinc signaling from dietary zinc deficiency. Brain Res Rev 62:33–44
Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5:33
Prasad AS (2014) Impact of the discovery of human zinc deficiency on health. J Trace Elem Med Biol 28:357–363
Peters S, Koh J, Choi DW (1987) Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science 236:589–593
Westbrook GL, Mayer ML (1987) Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328:640–643
Defazio T, Hablitz JJ (1988) Zinc and zolpidem modulate mlPSPs in rat neocortical pyramidal neurons. J Neurophysiol 80:1670–1677
Takeda A, Shakushi Y, Tamano H (2015) Modification of hippocampal excitability in brain slices pretreated with low nanomolar concentration of Zn2+. J Neurosci Res 93:1641–1647
Klingauf J, Kavalali ET, Tsien RW (1998) Kinetics and regulation of fast endocytosis at hippocampal synapses. Nature 394:581–585
Zakharenko SS, Zablow L, Siegelbaum SA (2001) Visualization of changes in presynaptic function during long-term synaptic plasticity. Nat Neurosci 4:711–717
Minami A, Sakurada N, Fuke S, Kikuchi K, Nagano T, Oku N, Takeda A (2006) Inhibition of presynaptic activity by zinc released from mossy fiber terminals during tetanic stimulation. J Neurosci Res 83:167–176
Takeda A, Fuke S, Minami A, Oku N (2007) Inhibition of presynaptic activity by zinc released from mossy fiber terminals during tetanic stimulation. J Neurosci Res 85:1310–1317
Takeda A, Fuke S, Tsutsumi W, Oku N (2007) Negative modulation of presynaptic activity by zinc released from Schaffer collaterals. J Neurosci Res 85:3666–3672
Kwak S, Weiss JH (2006) Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol 16:281–287
Takeda A, Tamano H (2015) Regulation of extracellular Zn2+ homeostasis in the hippocampus as a therapeutic target for Alzheimer’s disease. Expert Opin Ther Targets 19:1–8
Suzuki M, Fujise Y, Tsuchiya Y, Tamano H, Takeda A (2015) Excess influx of Zn2+ into dentate granule cells affects object recognition memory via attenuated LTP. Neurochem Int 87:60–65
Grabrucker AM, Knight MJ, Proepper C, Bockmann J, Joubert M, Rowan M, Nienhaus GU, Garner CC et al (2011) Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J 30:569–581
Sindreu C, Palmiter RD, Storm DR (2011) Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory. Proc Natl Acad Sci U S A 108:3366–3370
Takeda A (2014) Significance of Zn2+ signaling in cognition: insight from synaptic Zn2+ dysfomeostasis. J Trace Elem Med Biol 28:393–396
Takeda A, Tamano H, Ogawa T, Takada S, Nakamura M, Fujii H, Ando M (2014) Intracellular Zn2+ signaling in the dentate gyrus is required for object recognition memory. Hippocampus 24:1404–1412
Ceccom J, Halley H, Daumas S, Lassalle JM (2014) A specific role for hippocampal mossy fiber’s zinc in rapid storage of emotional memories. Learn Mem 21:287–297
Sindreu CB, Varoqui H, Erickson JD, Perez-Clausell J (2003) Boutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus. Cereb Cortex 13:823–829
Ueno S, Tsukamoto M, Hirano T, Kikuchi K, Yamada MK, Nishiyama N, Nagano T, Matsuki N et al (2002) Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits. J Cell Biol 158:215–220
Takeda A, Tamano H, Ogawa T, Takada S, Ando M, Oku N, Watanabe M (2012) Significance of serum glucocorticoid and chelatable zinc in depression and cognition in zinc deficiency. Behav Brain Res 226:259–264
Varea E, Ponsoda X, Molowny A, Danscher G, Lopez-Garcia C (2001) Imaging synaptic zinc release in living nervous tissue. J Neurosci Methods 110:57–63
Danscher G, Stoltenberg M (2005) Zinc-specific autometallographic in vivo selenium methods: tracing of zinc-enriched (ZEN) terminals, ZEN pathways, and pools of zinc ions in a multitude of other ZEN cells. J Histochem Cytochem 53:141–153
Li Y, Hough CJ, Frederickson CJ, Sarvey JM (2001) Induction of mossy fiber → CA3 long-term potentiation reguires translocation of synaptically released Zn2+. J Neurosci 21:8015–8025
Vogt K, Mellor J, Tong G, Nicoll R (2000) The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron 26:187–196
Izumi Y, Auberson YP, Zorumski CF (2006) Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors. J Neurosci 26:7181–7188
Takeda A, Fuke S, Ando M, Oku N (2009) Positive modulation of long-term potentiation at hippocampal CA1 synapses by low micromolar concentrations of zinc. Neuroscience 158:585–591
Nagappan G, Woo NH, Lu B (2008) Ama “zinc” link between TrkB transactivation and synaptic plasticity. Neuron 57:477–479
Pan E, Zhang XA, Huang Z, Krezel A, Zhao M, Tinberg CE, Lippard SJ, McNamara JO (2011) Vesicular zinc promotes presynaptic and inhibits postsynaptic long-term potentiation of mossy fiber-CA3 synapse. Neuron 71:1116–1126
Lorca RA, Rozas C, Loyola S, Moreira-Ramos S, Zeise ML, Kirkwood A, Huidobro-Toro JP, Morales B (2011) Zinc enhances long-term potentiation through P2X receptor modulation in the hippocampal CA1 region. Eur J Neurosci 33:1175–1185
Takeda A, Suzuki M, Tempaku M, Ohashi K, Tamano H (2015) Influx of extracellular Zn2+ into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation. Neuroscience 304:209–216
Hershey CO, Hershey LA, Varnes A, Vibhakar SD, Lavin P, Strain WH (1983) Cerebrospinal fluid trace element content in dementia: clinical, radiologic, and pathologic correlations. Neurology 33:1350–1353
Michalke B, Nischwitz V (2010) Review on metal speciation analysis in cerebrospinal fluid-current methods and results: a review. Anal Chim Acta 682:23–36
Gellein K, Skogholt JH, Aaseth J, Thoresen GB, Lierhagen S, Steinnes E, Syversen T, Flaten TP (2008) Trace elements in cerebrospinal fluid and blood from patients with a rare progressive central and peripheral demyelinating disease. J Neurol Sci 266:70–78
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Takeda, A., Tamano, H. Significance of Low Nanomolar Concentration of Zn2+ in Artificial Cerebrospinal Fluid. Mol Neurobiol 54, 2477–2482 (2017). https://doi.org/10.1007/s12035-016-9816-3
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DOI: https://doi.org/10.1007/s12035-016-9816-3